CN113318121B - Medicine for treating diabetic retinopathy and preparation method thereof - Google Patents

Abstract

The present invention discloses a medicament for treating diabetic retinopathy comprising chondroitin sulfate and vitamin C as active ingredients and a method for preparing the same. The medicine of the invention is administrated by the combination of chondroitin sulfate and vitamin C in the form of eye drops, and can improve the retinal edema of patients and improve the operation treatment effect simultaneously under the condition of combined operation treatment.

Description

Medicine for treating diabetic retinopathy and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a medicine for treating diabetic retinopathy and a preparation method thereof.

Background

Diabetes is a disorder in which the body is unable to properly metabolize carbohydrates (e.g., food starch, sugar, cellulose). The disease is characterized by excess sugar in the blood (hyperglycemia) and urine, inadequate production and/or utilization of islets, and thirst, hunger, and weight loss. Diabetes affects approximately 2% of the population. Wherein 10-15% of the total weight of the composition is insulin-dependent (type I) diabetes mellitus, and the balance is non-insulin-dependent (type II) diabetes mellitus.

Diabetic Retinopathy (DR) is the most important manifestation of diabetic microangiopathy, is a fundus lesion with specific changes, and is one of the serious complications of diabetes. Clinically, according to whether retinal neovascularization appears or not as a mark, diabetic retinopathy without retinal neovascularization is called non-proliferative diabetic retinopathy (NPDR) (or simple type or background type), and diabetic retinopathy with retinal neovascularization is called Proliferative Diabetic Retinopathy (PDR). Diabetic retinopathy is a special microvascular complication of both type I and type II diabetes. After 20 years of diabetes, nearly all patients with type I diabetes and more than 60% of patients with type II diabetes have some degree of retinopathy. In addition, retinopathy develops earlier and more severely in diabetic patients with high systolic blood pressure. On average, careful eye examination reveals mild retinal abnormalities about seven years after the onset of diabetes, but visual acuity-threatening impairments usually do not occur until long thereafter. Retinopathy can lead to blindness at a later stage. In developed countries, this is the second leading cause of acquired blindness following macular degeneration in the elderly. It is estimated that the risk of blindness in diabetic patients is 25 times greater than in the general population. There is currently no prophylactic or therapeutic pharmacological treatment for this complication. The only treatment is laser photocoagulation or vitrectomy in the most severe cases.

Diabetes patients mainly have abnormal insulin metabolism, which causes the microcirculation change of eye tissues, nerves and blood vessels, and damages to the nutrition and visual functions of eyes. The microvessels are microvessels and capillary networks which are arranged between arterioles and venules, have a lumen of less than 100-150 mu m, and are places for exchanging substances between tissues and blood. Vascular endothelial cell dysfunction is caused by changes in blood composition of diabetic patients, which impairs the blood-retinal barrier. The association between retinal capillary endothelial cytochrome epithelial cells is disrupted, resulting in leakage of small blood vessels. The microvascular lesions of diabetic patients mainly occur in retina and kidney, and are the main causes of blindness, renal failure and death.

In proliferative retinopathy, retinal damage stimulates the growth of new blood vessels. Neovascularization is detrimental to the retina, which can cause fibroplasia and sometimes can also lead to retinal detachment. New blood vessels can also grow into the vitreous, causing the vitreous to bleed. Proliferative retinopathy is more harmful to vision than non-proliferative retinopathy, which can lead to severe vision loss and even complete blindness. If found early, diabetic retinopathy can be treated by laser photocoagulation. For diabetic retinopathy, the basic indication for vitrectomy is vitreous hemorrhage and severe proliferative lesions. It is generally accepted that vitrectomy is required for patients with extensive vitreous hemorrhage for more than 3 months and who cannot spontaneously absorb the hemorrhage. However, when surgical treatment is adopted, how to improve retinal edema, lower intraocular pressure and improve vision of patients still remains a technical problem to be solved urgently.

The clinical effect of combined fundus laser therapy and ranibizumab on treating Diabetic Retinopathy (DR) is discussed in winter; the method comprises the following steps: selecting 68 DR patients accepted by the first hospital in the mountain area of Beijing city from 6 months to 5 months in 2017 as study objects; the 68 patients were divided into a control group (n-34) and an observation group (n-34); fundus laser therapy was used for control patients; treating patients in the observation group by combining fundus laser therapy and ranibizumab; then, carrying out the operation; comparing the treatment effect of the two groups of patients, the time for improving the symptoms of the retinal edema and the occurrence of eye complications and systemic adverse reactions of the retinal edema; as a result: after treatment; compared to control patients; the total effective rate of the treatment of the patients in the observation group is higher; the time for improving the symptoms of retinal edema is shorter; p < 0.05; during the treatment period; the two groups of patients do not have serious eye complications and systemic adverse reactions; and (4) conclusion: the effect of treating DR by combining fundus laser therapy and ranibizumab is remarkable; can effectively improve the symptoms of retinal edema of patients; and has high safety. The results of the relevant studies are reported in "the effect of combined fundus laser therapy and ranibizumab for treating diabetic retinopathy" J. 27-28.

Guo Yang et al investigated the effect of anti-Vascular Endothelial Growth Factor (VEGF) injection on the therapeutic effect of diabetic retinopathy prior to minimally invasive vitrectomy. Method 200 diabetic retinopathy patients who received treatment during 2016, 1 month to 2017, 12 months were randomly screened and divided into an observation group (n-100) and a control group (n-100) according to a double blind method. Two groups of patients are treated by minimally invasive vitreous surgery, the observation group of patients is punctured in the vitreous cavity and injected with 1mL of ranibizumab 3-5 days before the vitrectomy, and the control group does not adopt any operation. The treatment effect of the two groups of patients was evaluated, and the change of vision and intraocular pressure before and after the operation was analyzed. The total effective rate of the result observation group is higher than that of the control group; after treatment, the intraocular pressure and vision improvement conditions of the observation group are obviously better than those of the control group, and the difference has statistical significance (P < 0.05). Conclusion before minimally invasive vitreous surgery is performed to treat diabetic retinopathy, the anti-VEGF medicament is injected, so that the surgical treatment effect can be remarkably improved, the symptoms of patients are improved, the prognosis is promoted, and the application is worthy. Relevant study results are published in "investigating the effect of pre-operative injection of VEGF antibody on minimally invasive vitrectomy for the treatment of diabetic retinopathy" [ J ] clinical study, 2019,27 (06): 24-25.

Although the prior art has reported that certain drugs may be used in combination with surgery to treat diabetic retinopathy, there remains a need in the art for further improvements. For example, how to improve retinal edema of a patient and improve the effect of surgical treatment simultaneously still remains a technical problem to be solved by those skilled in the art.

Disclosure of Invention

Based on the above background, the technical problem to be solved by the present invention is to provide a medicine for treating diabetic retinopathy and a preparation method thereof. In order to realize the purpose of the invention, the following technical scheme is adopted:

the present invention relates, in one aspect, to a medicament for treating diabetic retinopathy, comprising chondroitin sulfate and vitamin C as active ingredients. The invention can improve the retinal edema of a patient and improve the operation treatment effect simultaneously under the condition of combined operation treatment by the combination of chondroitin sulfate and vitamin C.

In a preferred embodiment of the present invention, the weight ratio of chondroitin sulfate to vitamin is 4-6: 1.

in another preferred embodiment of the present invention, the drug is an eye drop.

In a preferred embodiment of the invention, the medicament further comprises sodium chloride, polyoxyethylene hydrogenated castor oil 60 and water.

In a preferred embodiment of the present invention, the formulation of the medicament is a composition comprising per 100 mL:

in another aspect, the invention relates to a method for preparing the above drug, which comprises mixing the components uniformly to obtain the target drug.

In another aspect, the invention also relates to the use of the above medicament in the treatment of diabetic retinopathy.

In a preferred embodiment of the invention, the medicament is for improving retinal edema in a patient with simple minimally invasive vitrectomy diabetic retinopathy.

In a preferred embodiment of the invention, the medicament is for improving the vision level of a patient with simple minimally invasive vitrectomy diabetic retinopathy.

In a preferred embodiment of the invention, the medicament is for reducing intraocular pressure in a patient with simple minimally invasive vitrectomy diabetic retinopathy.

Advantageous effects

The medicine of the invention is administrated by the combination of chondroitin sulfate and vitamin C in the form of eye drops, and can improve the retinal edema of patients and improve the operation treatment effect simultaneously under the condition of combined operation treatment. It is presumed that vitamin C can regulate the pH of the eye drops and can also act synergistically with chondroitin sulfate to inhibit retinal edema.

Detailed Description

In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.

Example 1: preparation of a medicament

The medicament is prepared according to the following formula:

on a sterile operating table at room temperature, firstly adding the polyoxyethylene hydrogenated castor oil 60 into deionized water, uniformly mixing, then sequentially adding the chondroitin sulfate, the vitamin C and the sodium chloride, and uniformly mixing to obtain the target medicament.

Pharmacodynamic experiment

One, general data

Randomly screening 180 diabetic retinopathy patients who receive treatment in the first hospital affiliated to the university of traditional Chinese medicine in Heilongjiang during the period from 2 months in 2019 to 2 months in 2020, and meeting the standard:

1) patients with type 2 diabetes have good blood sugar control, and the content of glycosylated hemoglobin is less than or equal to 10 percent;

2) DME that accumulates in the fovea;

3) foveal retinal thickness (CMT) > 250 microns;

4) refractive interstitial turbidity or miosis of the eye fundus for examination is not influenced;

5) macular edema without other causes;

6) the follow-up period is for surgery to treat diabetic retinopathy.

Exclusion criteria:

1) patients with combined malignant tumors or tumor metastases;

2) there are contraindications for surgery.

The treatment group (n 60), the positive control group (n 60) and the negative control group (n 60) are divided according to a double-blind method, and the general data of the three groups of patients have no significant difference (P > 0.05).

The study was approved by the institutional ethics committee and patient data were obtained and signed with consent by the patient or his family members.

Second, method

Patients in the negative control group underwent simple minimally invasive vitrectomy. The patient takes a horizontal position, is anesthetized by lidocaine, is subjected to 23G scleral channel excision of vitreous body, is subjected to removal of a proliferation membrane before retina, is subjected to retinal photocoagulation, intraocular photocoagulation and silicone oil filling according to the disease condition of the patient, and is injected with 0.3mL of dexamethasone and 0.6mL of tobramycin under the conjunctiva. After operation, the skin around the eyes is wiped by a 75% ethanol cotton ball, the antibiotic eye ointment is coated on the conjunctival inner capsule, and the affected eyes are covered by the CAD application.

The patients in the treatment group also performed simple minimally invasive vitreous surgery in the same manner as the negative control group. The medicine prepared in the example 1 is dripped into the affected eye 3d before operation and 5d after operation, 3-5 times/d.

The positive control group also performed a simple minimally invasive vitreous surgery in the same manner as the negative control group. Dripping compound chondroitin sulfate eye drops (each 10 ml contains 50 mg of chondroitin sulfate and 10 mg of taurine. auxiliary materials comprise potassium chloride, sodium chloride, calcium chloride, disodium hydrogen phosphate, L-mint, D-camphor, 50 parts of concentrated benzalkonium chloride solution, disodium edetate and polyoxyethylene hydrogenated castor oil 60) into affected eyes 3D before operation and 5D after operation for 3-5 times per day.

Third, observe the index

The treatment effect of three groups of patients was evaluated, and the change of intraocular pressure and vision before and after the operation was recorded. The curative effect evaluation is divided into obvious effect, effective effect and ineffective effect according to the vision improvement condition and symptom improvement condition of the patient with the visual acuity chart of the international standard, and the obvious effect is as follows: the symptoms of the patient such as fundus oozing blood, yellow spots, edema and the like completely disappear, and the vision returns to normal; the method has the following advantages: the clinical symptoms of the patients are obviously improved, and the eyesight is obviously improved; and (4) invalidation: all do not meet the above requirements. Total effective rate (effective + effective)/total number of cases × 100%.

The retinal thickness (MRT) of the Macular region is checked by OCT, the average retinal thickness in the range of 1mm in the central region of the macula lutea is detected, the normal condition is that the MRT is less than or equal to 250 mu m, the moderate edema is that the MRT is less than 500 mu m when the MRT is less than 250 mu m, and the severe edema is that the MRT is more than or equal to 500 mu m.

Fourth, statistical method

The data were analyzed using SPSS statistical software, and the data were expressed as mean. + -. standard deviation, the comparisons between groups were by t-test, the comparisons between groups were by Kruskal-wallis test, and the differences were statistically significant with P < 0.05.

Fifth, experimental results

5.1 the results of the clinical efficacy comparisons of the three groups of patients are shown in Table 1. The results show that the total treatment effective rate of the patients in the treatment group and the negative control group is 98.3 percent and 93.3 percent respectively, the comparison difference between the two groups has statistical significance (P is less than 0.05), and the comparison difference between the positive control group and the negative control group has no statistical significance (P is more than 0.05).

TABLE 1 macular foveal thickness (DMT) comparison (x + -s)

The results of the improvement of vision and intraocular pressure before and after the operation of three groups of patients are shown in Table 2. The results show that the comparison of the vision and intraocular pressure of three groups of patients has no significant difference before treatment (P is more than 0.05); after treatment, all indexes of three groups of patients are obviously improved compared with those before treatment, the treatment group is obviously superior to a negative control group and a positive control group, and the difference has statistical significance (P is less than 0.05).

TABLE 2 macular foveal thickness (DMT) comparison (x + -s)

5.3 three groups of patients had improved macular foveal thickness (DMT) as shown in Table 3. The results showed no significant difference in DMT comparison for three groups of patients before treatment (P > 0.05); after treatment, DMT indexes of three groups of patients are obviously improved compared with those before treatment, and the treatment group is obviously superior to a negative control group and a positive control group, and the difference has statistical significance (P is less than 0.05).

TABLE 3 macular foveal thickness (DMT) comparison (x + -s)

The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims (8)

1. A medicament for treating diabetic retinopathy, comprising chondroitin sulfate and vitamin C as active ingredients in a weight ratio of 4-6: 1, the medicine is eye drops.

2. The medicament of claim 1, further comprising sodium chloride, polyoxyethylene hydrogenated castor oil 60, and water.

3. A medicament for the treatment of diabetic retinopathy, said medicament being formulated to contain per 100 mL:

4. a process for the preparation of a medicament as claimed in any one of claims 1 to 3, which process comprises mixing the components together to give the desired medicament.

5. Use of a medicament according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of diabetic retinopathy.

6. The use according to claim 5, for the improvement of retinal edema in a minimally invasive vitreous surgery diabetic retinopathy patient alone.

7. The use according to claim 5, for improving the vision level in a minimally invasive vitrectomy-only diabetic retinopathy patient.

8. The use according to claim 5, for reducing intraocular pressure in a patient with minimal invasive vitrectomy-only diabetic retinopathy.